Antibiotics are an effective tool in the treatment of infectious diseases. From the development of antibiotic therapy to the late 1980s there was almost complete control over bacterial infections in developed countries. However, in response to the pressure of antibiotic usage, multiple resistance mechanisms have become widespread and are threatening the clinical utility of anti-bacterial therapy. The increase in antibiotic resistant strains has been particularly common in major hospitals and care centers. The consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalization, and an increase in treatment costs.
Extensive use of antibiotics, including some aminoglycosides such as streptomycin and kanamycin, began in the 1950's. As the problem of global antibiotic resistance has continued to increase, antibiotics, have assumed increasing importance in clinical practice. For some aminoglycosides, their broad antimicrobial spectrum, rapid bactericidal action, and synergistic action with other drugs made them especially useful in the treatment of serious nosocomial infections (Umezawa, H.; Hooper, I. R., Aminoglycoside Antibiotics, Publisher: Springer Verlag 1982; Price K E, Godfrey J C, Kawaguchi H. Effect of structural modifications on the biological properties of aminoglycoside antibiotics containing 2-deoxystreptamine. In: Perlman D, editor. Structure-activity relationships among the semisynthetic antibiotics. New York: Academic Press; 1977. p. 239-375; Aminocyclitol Antibiotics, ACS Symposium Series 125, June 1980, K. L. Rhinehart, T. Suami (Editors); and Wright, G. D. et al., Aminoglycoside antibiotics. Structures, functions, and resistance. Adv Exp Med Biol 1998, 456, 27-69).
However, the usefulness of certain aminoglycosides in medicine has been impaired by several factors. For example, the development of microbial resistance has reduced the effectiveness of some aminoglycoside antibiotics. In some cases, microbial resistance is mediated by bacterial enzymes modifying the structure of the aminoglycoside (Mingeot-Leclercq, M. P. et al., “Aminoglycosides: activity and resistance”, Antimicrob. Agents Chemother. (1999), 43(4), 727-737; Magnet S., Blanchard, J. S., “Molecular insights into aminoglycoside action and resistance”, Chem. Rev., (2005), 105(2), 477-498; Vakulenko, S. B.; and Mobashery, S., “Versatility of Aminoglycosides and Prospects for Their Future” Clin. Microbiol. Rev., (2003), 16, 430-450; and Kotra, L. P. et al., “Aminoglycoside: perspectives on mechanisms of action and resistance and strategies to counter resistance”, Antimicrob. Agents Chemother., (2000), 44(12), 3249-3256).
In addition, the use of some aminoglycoside antibiotics, such as amikacin, netilmicin, arbekacin, and etimicin, is limited due to toxicity considerations (Rougier, F. et al., Aminoglycoside dosages and nephrotoxicity: quantitative relationships. Clin Pharmacokinet (2003), 42, (5), 493-500; and Rougier, F. et al., Aminoglycoside nephrotoxicity. Curr Drug Targets Infect Disord (2004), 4, (2), 153-62).
Thus, there is a need for new aminoglycoside antibiotics.